Adaptive brain plasticity after stroke is critically dependent upon behavioral experience. Manipulations of experience, including rehabilitative training, are emerging as a core strategy for driving functionally appropriate brain reorganization after brain damage. However, learning-induced brain changes can be laborious to achieve, perhaps especially when the circuits being driven to reorganize are dysfunctional due to denervation and other injury-induced degenerative changes. There is much room for further improvement. This proposal focuses on a new direction in facilitating "re-learning" after stroke, that of combining rehabilitative training with electrical stimulation of remaining cortex of a stroke-affected hemisphere. In animal models of focal cortical infarcts, this approach improves and prolongs the functional benefits of a period of motor rehabilitative focused on the impaired upper extremity. However, we have practically no understanding of how and why this works. We propose a series of initial experiments to improve our understanding of the neural basis of the behavioral improvements resulting from combining motor cortical stimulation (CS) with motor training. The central hypothesis is that CS improves behavioral outcome by facilitating learning-induced neural plasticity in the motor cortex and connected regions. This will be investigated in rats with unilateral ischemic infarcts of the sensorimotor cortex and rehabilitative training in skilled reaching to improve forelimb function. There are three specific aims. Aim 1 is test the hypothesis that facilitation of training-induced neural plasticity in remaining motor cortex mediates the functional efficacy of CS. Aim 2 is to test the hypothesis that CS+motor training results in persistent synaptic structural plasticity within motor cortex in comparison to motor training alone. Aim 3 is to test the hypotheses that CS+motor training promotes plasticity and lessens long-term deterioration in motor cortical efferent regions compared with motor training alone. These hypotheses will be tested with a combination of sensitive behavioral measures, quantitative light and electron microscopy to assay changes in neuronal activity and synaptic structure as well as intracortical microstimulation (ICMS) mapping to reveal the functional integrity and organization of motor cortex. The immediate goal is to obtain data on the characteristics of CS-induced plasticity that are useful both for guiding more detailed future studies and for its clinical applications. The more general goal is to obtain a sufficient understanding of CS mechanisms to improve the ability to use it and related therapies to improve function after stroke. PUBLIC HEALTH RELEVANCE: Physical therapy and rehabilitation can be used to improve function after stroke but, even with extreme effort, such treatments can be limited in efficacy. Cortical stimulation (CS) has recently been found to enhance motor rehabilitative training effects in rats and monkeys. By gaining knowledge of the neural mechanisms underlying the beneficial effects of CS, we hope to better understand how to use this and related therapies to optimize functional outcome after stroke.